Glycosaminoglycans (GAGs) are naturally occurring linear polysaccharides encountered both in the extracellular matrix and on cell surfaces where they form a carbohydrate coating referred to as the glycocalyx. GAGs are involved in a wide array of physiological processes, including cell proliferation and migration, as well as modulation of angiogenesis and inflammatory responses (Clowes, A. W. and Karnovsky, M. S. (1977) Nature 265; Jackson, R. L. et al. (1991) Physiol. Rev. 71:481; Linhardt, R. J. et al. (1996) In Biomedical Functions and Biotechnology of Natural and Artificial Polymers, ATL Press, p. 45). The diverse bioactivities of GAGs are a consequence of unique binding sequences that facilitate local sequestration of biologically active proteins, such as growth factors and antithrombin III. In this manner, GAGs function as delivery vehicles for the controlled local release of a variety of proteins and; in select circumstances, potentiate the activity of the bound protein (Kjellen, L. and Lindahl, U. (1991) Ann. Rev. Biochem. 60:443; Faham, S. et al. (1996) Science 271:1116; Bitomsky, W. and Wade, R. C. (1999) J. Am. Chem. Soc. 121:3004). Glycopolymers can induce affinity toward proteins such as lectins, and to viruses, due to multivalent recognition, known as the “cluster effect.” (Lee, Y. C. and Lee, R. T., Eds. (1994) Neoglycoconjugates: Preparation and applications; Academic Press, San Diego, Calif.; Roy, R. (1996) Current Opinion in Structural Biology 6:692–702.)
The inability to generate GAGs through recombinant genetic engineering strategies, combined with the inherent complexity that has been associated with their direct chemical synthesis, has stimulated the development of a variety of biomimetic synthetic approaches for the generation of carbohydrate-based macromolecules (Toshima, K. and Tatsuta, K. (1993) Chem. Rev. 93:1503; Roy, R. (1996) Curr. Opin. Struct. Biol. 6:692; and Roy, R. (1997) Topics Curren. Chem. 187:241).
Smaller oligosaccharide sequences may be responsible for the unique biological activities of the parent polysaccharides (Van Boeckel, C. A. A. et al. (1993) Chem. Int. Ed. Engl. 32:1671; Westerduin, P. et al. (1996) Chem. Int. Ed. Engl. 35:331; Petitou, M. et al. (1998), Chem. Int. Ed. 37:3009; Petitou, M. et al. (1999) Nature 398:417; Westman, J. et al. (1995) Carbohydr. Chem. 14:95; and Ornitz, D. M. et al. (1995) Science 268:432). While advantages of such an approach exist, an inherent limitation is the loss of spatially controlled organization of multiple target saccharide sequences. Indeed the observation of enhanced protein binding affinity derived from multivalent oligosaccharide ligands has been termed the “cluster glycoside effect” (Lee, Y. C. In Synthetic Oligosaccharides: Indispensable Probes for the Life Sciences, ACS Symposium Series 560, Washington, D.C. 1994, Chapter 1, p. 6; Dimick, S. M. et al. (1999) J. Am. Chem. Soc. 121:10286; and Suda, Y. et al. (2000) Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.) 41(2):1624).
An alternative glycomimetic strategy has consisted of the design of synthetic polymers that contain a hydrocarbon backbone with biologically active pendent saccharides. Fundamental studies on the synthesis and properties of model “glycopolymers” have proven to be useful in the characterization of specific biomolecular recognition processes (Miyata, T. and Nakamae, K. (1997) Trends Polym. Sci. 5:198).
Optimization of glycopolymer properties has required the utilization of biomolecular architectures that exhibit low fluctuations both in polymer size and in composition. A large variety of “living”/controlled polymerization techniques have recently emerged for this purpose, including ring-opening polymerization of sugar-substituted N-carboxyanhydrides (Aoi, K. et al. (1992) Macromolecules 25:7073; and Aoi, K. et al. (1994) Macromolecules 27:875); ring-opening metathesis polymerization (ROMP) of sugar-derivatized norbornenes (Fraser, C. and Grubbs, R. H. (1995) Macromolecules 28:7248; Nomura, K. and Schrock, R. R. (1996) Macromolecules 29;540); cationic polymerization of saccharide-carrying vinyl ethers (Minoda, M. et al. (1995) Macromol. Symp. 99:169; Yamada, K. et al. (1997) J. Polym. Sci. Part A: Polym. Chem. 35:751; and Yamada, K. et al. (1999) Macromolecules 32:3553); anionic polymerization of styrene derivatives containing monosaccharide residues (Loykulnant, S. et al. (1998) Macromolecules 31:9121; and Loykulnant, S. and Kirao, A. (2000), Macromolecules 33:4757); nitroxide-mediated free-radical polymerization of sugar-carrying styryl (Ohno, K. et al. (1998) Macromolecules 31:1064; and Ohno, K. et al. (1998) Macromol. Chem. Phys. 199:2193); and acryloyl (Ohno, K. et al. (1999) Macromol. Chem. Phys. 200:1619); monomers, as well as Atom Transfer Radical Polymerization (ATRP) of carbohydrate-based methacrylates (Ohno, K. et al. (1998) J. Polym. Sci., Part A: Polym. Chem. 36:2473; Ejaz, M. et al. (2000) Macromolecules 33:2870; Bon, S. A. F. and Haddleton, D. M. (1999) Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.) 40(2):248; and Marsh, A. et al. (1999) J. Macromolecules 32:8725). Nevertheless, due to the incompatibility of hydroxyl groups from the saccharide moieties with either initiators or controlling agents, all of these approaches require the use of protected monomers and the subsequent deprotection of polymer chains to generate the desired glycopolymers.
All publications referred to herein are incorporated herein in their entirety to the extent not inconsistent herewith.